IE47073B1 - Alpha amino-acids, compositions and process for preparing said compounds - Google Patents

Alpha amino-acids, compositions and process for preparing said compounds

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Publication number
IE47073B1
IE47073B1 IE1079/78A IE107978A IE47073B1 IE 47073 B1 IE47073 B1 IE 47073B1 IE 1079/78 A IE1079/78 A IE 1079/78A IE 107978 A IE107978 A IE 107978A IE 47073 B1 IE47073 B1 IE 47073B1
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IE
Ireland
Prior art keywords
compounds
alpha
compound
benzylidene
diphenylmethylenedioxybenzyl
Prior art date
Application number
IE1079/78A
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IE781079L (en
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Merck & Co Inc
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Filing date
Publication date
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of IE781079L publication Critical patent/IE781079L/en
Publication of IE47073B1 publication Critical patent/IE47073B1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Abstract

alpha -Amino Acids, compositions and process for preparing said compounds alpha -ethynyl- and - alpha -vinyl-3,4-disubstituted pheynylalanines and esters thereof, have been prepared by reaction of methyl 3,4-dihydroxybenzoate with diphenyldichloromethane, reduction of the so obtained methyl 3,4-diphenylmethylene- dioxy- benzoate to 3,4-diphenylmethylenedioxybenzyl- alcohol, and transforming this to the benzylchloride. This 3,4-diphenylmethylenedioxybenzylchloride reacts with 1-trimethyl- silyl-N-benzylidene-3-aminoprop-1-yne to form 3-(3,4- diphenylmethylenedioxybenzyl) -1-trimethysilyl N-benzylidene-3- aminoprop-1-yne. …With methyl chloroformate this compound gives 3-carbomethoxy-3- (3, 4- diphenylmethylenedioxybenzyl-1-trimethylsilyl-N-benzylidene -3-aminoprop-1-yne. …The benzylidene-group, the trimethylsilyl-group and the diphenyl-methylene- group are removed, which results in the formation of alpha -ethynyl- 3,4-dihydroxy- phenylalanine. The alpha -vinyl- analog is obtained by hydrogenation of an intermediate. The compounds have a pharmaceutical activity.

Description

The present invention is concerned with a-ethynyl-and a-vinyl-3,4-disubstituted phenylalanines and especially the 3,4-dihydroxyphenylalanine species. α-Methy1-3,4-dihydroxyphenylalanine, particularly its L-isomer, is a known antihypertensive agent. (U.S. 2,868,818 U.S. 3,344,023). French Patent 185OM discloses a-C2 and higher alkyl-3,4-0R-phenylalanines. The α-ethyl derivative has antihypertensive activity.
Novel α-ethynyl-and a-vinyl-3,4-disubstituted phenylalanines have been discovered. These novel alanines have pharmaceutical activity including antihypertensive action.
SUMMARY OF THE INVENTION α-Ethynyl-and a-vinyl-3,4-di-0R-phenylalanines, esters thereof and their pharmaceutical use. -247073 DESCRIPTION OF THE INVENTION The present invention is embodied in aethynyl or α-vinyl phenylalanine compounds having the formula CH, ✓ NH2 O-R wherein L is -CsCH or -CH=CH2, R^ and R2 are independently selected from H and C2~Cg alkanoyl, and R is alkyl or H.
The pharmaceutically acceptable salts of the formula I compounds are also included. These salts generally are acid addition salts of suitable organic or inorganic acids. Preferred salts are the hydrohalides such as the hydrobromides, the hydrochlorides, the hydrogen iodides. Most preferred salts are the hydrochlorides.
The compounds of formula I have a chiral center and may occur in optically active forms, i.e., as optical isomers. These isomers are conventionally designated as D and L, d and 1, + and -, (S) and (R) or by a combination of these symbols.
Where the compound name or formula does not specify the isomer form, all forms are included, i.e., the individual isomers, mixtures thereof and racemates .
Of the isomers, the E-form is preferred. - 3 4 7 0 7 3 R may be H or a Cj-C^g alkyl gxcup. Examples of suitable alkyl groups are octadecyl, 2-ethylhexyl, lauryl, undecyl, methyl, isopropyl, or hexyl.
Preferred R groups are H and C^-Cg alkyl. Most . preferred R groups are H and ethyl.
R^ and R2 include H and C2~Cg alkanoyl groups. Examples of suitable alkanoyl groups are acetyl, pivaloyl·, 2-methylpropanoyl, or butanoyl. The most pre10 ferred Rj/R2 substituent is hydrogen.
A preferred class of compounds of the present invention is that having the formula CsCH n Ησ-Ζν-®2— cx HO-k^ *®2 0R II Especially preferred are formula II compounds 15 where R is hydrogen or C^-Cg alkyl, preferably ethyl.
The L-isomer form of the formula II compound is also more preferred. another preferred class of compounds 20 of the present invention is that having the formula III Especially preferred are the formula III compounds - 4 where R is hydrogen or C^-Cg alkyl, preferably ethyl.
The L-isomer form of the formula III compounds are also more preferred.
The compounds of the present invention have pharmaceutical activity especially as antihypertensive agents. Thus, the present compounds are useful for treating hypertension in humans.
Other biological activities of the present compounds include inhibition of 3,4-dihydroxyphenylalanine (dopa) decarboxylase.
For treating hypertension, the present compounds may be administered to the hypertensive patient orally, parenterally or via any other suitable administration route. Conventional dosage forms are used such as tablets, troches, capsules, liquid formulations, e.g., solutions, dispersions, emulsions , or elixirs.
Conventional compounding ingredients, i.e., diluents, carriers, etc. and conventional preparation procedures are utilized.
The daily dosage of the present compounds may be varied as required. In general, a daily dosage range for the hypertensive patient is about 50 mg. to about 5000 mg. A preferred daily dosage range is about 100 mg. to about 3500 mg. A more preferred daily dosage range is about 250 to about 1500 mg.
Compounds of the present invention may be prepared by any convenient process.
An especially useful process for preparing the compounds of formula I where R, R^ and R2 are hydrogen is by the hydrolysis of a compound having the formula CH IV . where L is -C=CH or -CH=CH2, R* is alkyl preferably C-j^-Cg alkyl, and Rg and R4 are groups, e.g., H, CHg or phenyl, which permit hydrolysis of the dioxy moiety. The hydrolysis is carried out using conventional reagents and conditions, for example using an acid such as HCl, HBr, HgPO^, in a suitable solvent such as water, or aqueous alkanols.
The hydrolysis may be carried out at room temperature or at elevated temperatures up to about 140°C. The reaction time will vary depending on other parameters such as temperature, etc.
Where R in formula I is an alkyl group, the compound is prepared by conventional esterification of the corresponding compound where R is H as illustrated by the following equation The pharmaceutically acceptable salts of the present compounds may be obtained directly from the hydrolysis reaction described above.
Such salts may also be obtained by treatment of the formula I free base with an appropriate acid under suitable conditions. - 6 47073 Where the compounds of the present invention are obtained as racemates, they may be separated into the individual enantiomers by conventional resolution techniques. Such techniques commonly involve the formation of salts of the present racemeic acids with optically active bases. The resolution is preferably carried out on the Ο,Ο,Ν-triacyl derivatives of the racemic acid mixture. These acyl derivatives are prepared by treatment of the free acid mixture with a suitable acylating agent as illustrated by the following equation: HO HO L I CH2-cnh2 (R -C ~^20 pyridine R=substituted or unsubstituted Cl"C6 alkyl The resolution procedure including hydrolysis of the resolved acylated acids is exemplified in U.S. 3,344,023.
Compounds of the present invention where R^ and R2 are lower alkanoyl are prepared by appropriately acylating the corresponding compound where R^ and R2 are each H, as illustrated by the following equation: - 7 47073 To prevent acylation of the a-NH2 group, the reaction may be carried out in an acid medium, e.g., glacial acetic acid. An example illustrating such an acylation system is in U.S. 3,983,138.
The following examples illustrate preparation of compounds of the present invention via a series of intermediate steps. All temperatures are °C. The symbol Ph represents the phenyl group in the formulae below: EXAMPLE 1 A.) A mixture of methyl 3,4-dihydroxybenzoate (8.40 g.j 50 mmol) and diphenyldichloromethane was stirred at 150 + 5° for 15 minutes. The mixture was cooled, taken up in benzene and the benzene solution washed with 5% aqueous KHCO3, saturated 7 0 7 3 aqueous NaCl, dried over MgSO4 and concentrated to dryness. The crystalline residue (m.p. 98100°) was recrystallized from hexane containing a little benzene to give pure methyl 3,4-diphenylmethylenedioxybenzoate (15.3 g., 96%) m.p. 103105°.
B.) Ph COOCH3 LiAlH4 Ph h2~OH — - —1 Ph Ph To a stirred suspension of 1.48 g LiAlH4 in 80 ml. of ether was added dropwise a solution of methyl 3,4-diphenylmethylenedioxybenzoate (13.09 g.; 39.4 mmol) in 80 ml. ether and 10 ml. tetrahydrofuran. The rate of addition was controlled to maintain the reaction mixture at a gentle reflux. The mixture was then refluxed 45 minutes. It was then cooled and 5 ml of ethyl acetate was added dropwise followed by 15 ml. of saturated aqueous Na2SO4 and about 5 g. anhydrous MgSO4· The mixture was filtered, the inorganic precipitate washed with 1:1 ether-benzene, and the combined filtrate and washings concentrated to dryness to give 11.65 g. of 3,4-diphenylmethylenedioxybenzyl alcohol as a colorless viscous oil which partially solidified on cooling.
On recrystallization from hexane-benzene an aliquot had m.p. 63-64°.
C.) ether > To a stirred solution of 11.6 g. (38 mmol) of 3,4-dipheny Imethylenedioxybenzyl alcohol in ether (80 ml.) and pyridine (0.6 ml.) at 20°C. was added dropwise a solution of SOCl2 in ether (40 ml.). The mixture was cooled to 0-5°C., and CH2CI2 and water were added. The layers were separated, and the organic layer was washed with water and saturated aqueous NaCl, dried over MgSO^ and concentrated to dryness to yield 3,410 diphenylmethylenedioxybenzyl chloride (11.43 g.) as a colorless viscous oil: tic (silica gel CH2C12: Rf0.8? ir (CCl^) no -0H-, nmr (CC14)£ 4.34 (s, 2H), 6.74 (d,j=8) 2h, 6.67 (s, lH), 7.1-7.6 (m, 10H).
D.) To a stirred solution of 1-trimethylsilyl-N-benzylidene-3-aminoprop-l-yne (7.6 0 9 g.r 34.4 mmol) in 106 ml. of tetrahydrofuran maintained at -78° under N2 was added dropwise 19.5 ml. of 1.63 N n-butyl lithium in hexane. To the stirred deep red solution was then added dropwise 11.43 g. (35.4 mmol) of 3,4-diphenylmethylenedioxybenzyl chloride in 35 ml. of tetrahydrofuran. After an additional 30 minutes at -78° water (25 ml.) was added dropwise, the mixture was warmed to 20°, 10% aqueous - 10 4 7 0 7 3 NH^Cl, solution was added and the layers were separated. The aqueous layer was washed twice with benzene, the combined organic phases were washed twice with cold 10% aqueous Nh^Cl, once with saturated NaCl solution, dried over Na2SO^ and concentrated to dryness to give 3-(3,4diphenylmethylenedioxybenzyl)-1-trimethylsilylN - benzylidene-3-aminoprop-l-yne as a viscous orange oil (18,86 g).
The mass spectrum showed a large molecular ion peak at 501.
To diisopropylamine (700 mg.) in 15 ml. tetrahydrofuran at -78° under N2 was added 3.8 ml. of 1.64 M n-butyllithium In hexane dropwise. After 5 minutes, 3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-l-yne (3.378 g.; 6.74 mmol) in 15 ml. tetrahydrofuran was added dropwise (10 minutes). After an additional 5 minutes, methyl ohloroformate (680 mg.) in tetrahydrofuran (10 ml.) was added dropwise (5 minutes).
After 40 minutes at -78° the solution was warmed to 0° and the color lightened from deep red to orange. After 10 minutes at 0°, water (5 ml.) was added dropwise followed by 10% agueous NH^Cl (30 ml.). The layers were separated and the mixture extracted as in the previous example, dried - 11 47073 over Na2SO4 and concentrated to dryness to give 3-carbomethoxy-3-(3,4-diphenylmethylenedioxybenzyl) - l-trimethylsilyl-N-benzylidene-3-aminoprop1-yne (3.645 g.) as an orange foam; mass spectrum M/e 559, large fragmentation peaks at 287 (base peak) and 272.
F.) COOCH1 3 (CH-),SiC=£C-C-N=CHPh J J Silica Gel CIi2 > Chromatography of crude 3-carbomethoxy3-(3,4-diphenylmethylenedioxybenzyl) 1-trimethylsilyl-N-benzylidene-3-arainoprop-l-yne (3.55 g.) over 180 g. of silica gel H eluting with 2% acetone in chloroform led to hydrolysis of the Schiff base protecting group to give the free amine, 3-carbomethoxy-3-(3,4-diphenylmethylenedica^en2yi)-l-fcrtaethylfeilyl-3-aniinproprl-yne (tic silica gel 3% acetone in CHClg Rp/-v. 2) Mass spec. M/e 471. - 12 4 7 0 7 3 To a solution of 3-carbomethoxy-3(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidine-3-aminoprop-l-yne (610 mg.) in 6 ml. of methanol under nitrogen at 20°c was added. 1.1 ml. of 1.6 M NaOCH-j in CH3OH. The solution was stirred 30 minutes, CH2C12 and cold water were added and the layers separated. The aqueous layer was washed with Cl^Clg and the combined CH2Cl2 phase washed with cold water and saturated NaCl solution, dried over Na^O^ and concentrated to dryness to give 3-carbomethoxy-3(3,4-diphenylmethylenedioxybenzyl)-3-aminoprop-1yne (505 mg.) as a viscous orange foam; nmr (CDC13) 1.80 (broad S,2H) 2.45 (s, lH) 3.10 (s,2H), 3.75 (s,3H) 6.79(d,j=5,2H), 6.75 (s, IH), 7.0-7.7 (m, 10H). - 13 47 073 Η.) COOCH, COOH I hc=ec-2 6n hc1 ecec-c-NH2.HC1 Ph ''Ph A solution of 3-carbomethoxy-3-(3,4diphenylmethylenedioxybenzyl)-3-aminoprop-lyne (230 mg.) in 6N HCl (15 ml.) was refluxed for 2 hours, cooled and extracted with CH2C12. The aqueous acid phase was taken to dryness to give a-ethynyl-3,4-dihydroxyphenylalanine hydrochloride (135 mg, 90%) tlc-n butanol :acetic acid: water 25:4:10 single spot 0.4; n-butanol:acetic acid:water:pyridine 15:3:12:10 single spot RF 0.6; mass spec. M+ 221; (DjO) £3.17 (s,2H), 3.22 (s,lH) 6.70 m,3H).
The HCl salt obtained in Example 1 H.) may be conventionally neutralised or treated with an HCl scavenger such as propylene oxide to obtain the corresponding free amino acid.
EXAMPLE 2 - 14 47073 Lindlar H2/catalyst quinoline,ethyl/ acetate A solution of 3-carbomethoxy-3-(3,4diphenylmethylenedioxybenzyl)-3-aminoprop-l-yne (90 mg.) in 10 ml. of ethyl acetate and 0.02 ml. quinoline was stirred in 1 atm of hydrogen over 20 mg. of Lindlar's catalyst [5%Pd-CaCO3 + Pb(OAc)2) at 25° until hydrogen uptake ceased.
The catalyst was removed by filtration and the filtrate taken to dryness. The nearly pure product, was purified by dry column chromatography on 10 g. of silica gel eluting with 15% acetone in chloroform to give pure 3-carbomethoxy-3-(3,4diphenylmethylenedioxybenzyl)-3-aminoprop-l-ene, mass spec. M+ 401; nmr (CDClg) 1.72 (s, 2H), 2.75 (d, J=14,1H), 3.18 (d,J=14.1H)-AB quartet 3.70 (s,3H), 5.17 (d,d,J=10,2,lH), 5.35 (d,d,J= 18,2,1H) 6.17 (d,d,J=18, 10, IH) 6.72-677 (m, 3H); 7.25-7,8 (mk 10 H). - 15 47073 Β.) COOCH. Ν HCl -> COOH Utilizing the procedure of Example 1 Η.), 3-carbomethoxy-3(3,4-diphenylmethylenedioxybenzyl)-3-aminoprop-l-ene was hydrolyzed to produce a-vinyl-3,4-dihydroxyphenylalanine hydrochloride, tlc-n-butanol, acetic acid:water; pyridine-15:3:12:10 Jsingle spot Rp~0.65; mass spec M 223:nmr(D20) <53.03 (d,J=15, 1H), 3,33(d,J=15, 1H) AB quartet, .35 (d,J=18, 1H); 5.50 (d,J=12, 1H), 6.18 (d,d,J= 18,12 1H), 6.6-7.1 (m 3H).
The HCl salt obtained in Example 2 B may be conventionally neutralized or treated with an HCl scavenger such as propylene oxide to obtain the corresponding free amino acid.

Claims (11)

1. CLAIMS -.1. Compounds having the formula wherein L is -C“CH or -CH=CH 2 , R^ and R 2 are independently selected from H and C^-Cg alkanoyl, and R is C^Cj^g alkyl or H.
2. The pharmaceutically acceptable salts of the Claim 1 compounds.
3. Compounds of Claim 1 having the Lisomer configuration.
4. compounds of Claim 1 wherein R^ and R 2 are both hydrogen.
5. Compounds of Claim 4 wherein R is hydrogen.
6. 3=CH, R is Compound of Claim 1 wherein L is ethyl and R^ and R 2 are both hydrogen. >1-70 73
7. Compound of Claim 1 wherein L is —C~CH, R^ and R 2 are both H and R is H having the L-isomer configuration.
8. Compounds of Claim 1 having the formula - 17 Λ 7 θ’ 7 3 CH—CH, ϊ/herein R^ and R 2 are both hydrogen and R is H or —C g alkyl.
9. Compound of Claim 8 wherein R is ethyl. 5 10. Compound of Claim 8 wherein R is H, having the Lisomer configuration. 11. Pharmaceutical composition containing a therapeutically effective amount of a compound of Claim 1 or a pharma ceutically acceptable salt thereof.
10. 12. A process for preparing a compound having the formula which comprises hydrolysing a compound having the formula L \0R wherein
11. 15 L is —C=CH or —CH=CH 2 , R is C^—C 18 alkyl and R 3 and are independently selected from the group consisting of H, CH 3 or a phenyl group. -184 7 0 7 3 R 13. is -CH 3 . The process of Claim 12 wherein L 14. is -C=CH. The process of Claim 13 wherein 15. The process of Claim 13 wherein L is -CH=CH 2 .
IE1079/78A 1977-06-01 1978-05-30 Alpha amino-acids, compositions and process for preparing said compounds IE47073B1 (en)

Applications Claiming Priority (1)

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US05/802,390 US4401676A (en) 1977-06-01 1977-06-01 Novel α-amino acids

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IE47073B1 true IE47073B1 (en) 1983-12-14

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EP (1) EP0000035B1 (en)
JP (1) JPS543036A (en)
DE (1) DE2861499D1 (en)
DK (1) DK240778A (en)
IE (1) IE47073B1 (en)
IT (1) IT7849636A0 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4182891A (en) * 1977-07-01 1980-01-08 Merrell Toraude Et Compagnie α-Acetylenic derivatives of α-amino acids
IE47082B1 (en) * 1977-07-01 1983-12-14 Merrell Toraude & Co -acetylenic amino acids
CA1157030A (en) * 1977-07-01 1983-11-15 Brian W. Metcalf .alpha.-VINYL AMINO ACIDS
DK309579A (en) * 1978-07-24 1980-02-22 Merck & Co Inc PROCESS FOR THE PREPARATION OF ALPHETHYNYLAMINO ACIDS AND ESTERS THEREOF
DK309679A (en) * 1978-07-24 1980-02-22 Merck & Co Inc PROCESS FOR THE PREPARATION OF ALFAVINYLAMINO ACIDS AND ESTERS THEREOF
DK309379A (en) * 1978-07-24 1980-01-25 Merck & Co Inc METHOD OF PREPARING AMINO ACIDS AND AMINO ACID EASTERS
JPH02138A (en) * 1987-09-18 1990-01-05 Banyu Pharmaceut Co Ltd L-dopa derivative
JPH09501178A (en) * 1993-08-06 1997-02-04 スミスクライン・ビーチャム・コーポレイション Endothelin receptor antagonist
FR2724654B1 (en) * 1994-09-16 1997-12-12 Roussel Uclaf NEW GALLIC ACID DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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Publication number Priority date Publication date Assignee Title
US2868818A (en) * 1953-12-15 1959-01-13 Merck & Co Inc Alpha methyl phenylalanines
NL124121C (en) * 1960-04-08
NL129419C (en) * 1960-08-19
FR1850M (en) * 1961-02-24 1963-06-10 Merck & Co Inc Phenylalanine derivatives.
CH441362A (en) * 1963-12-24 1967-08-15 Hoffmann La Roche Process for the preparation of phenylalanine derivatives
US3395176A (en) * 1964-03-06 1968-07-30 Merck & Co Inc Alpha-hydroxymethylphenylalanine compounds
US3488363A (en) * 1965-10-22 1970-01-06 Merck & Co Inc Preparation of alpha-methylphenyl alanines
CH475193A (en) * 1966-06-07 1969-07-15 Hoffmann La Roche Process for the preparation of phenylalanine derivatives
US3714241A (en) * 1969-10-29 1973-01-30 Merck & Co Inc PREPARATION OF alpha -METHYL-3,4-DISUBSTITUTED PHENYLALANINES
JPS5025465B1 (en) * 1970-12-29 1975-08-23
US4022910A (en) * 1972-12-22 1977-05-10 Richardson-Merrell Inc. L-3-hydroxymethyltyrosine and salts thereof for lowering blood pressure
US3983138A (en) * 1973-09-25 1976-09-28 Merck & Co., Inc. Amino acid esters
US4051251A (en) * 1976-02-13 1977-09-27 Merck & Co., Inc. Novel anti-hypertensive compositions

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EP0000035B1 (en) 1982-01-06
DK240778A (en) 1979-01-12
IT7849636A0 (en) 1978-05-31
JPS543036A (en) 1979-01-11
IE781079L (en) 1978-12-01
US4401676A (en) 1983-08-30
DE2861499D1 (en) 1982-02-25
EP0000035A1 (en) 1978-12-20

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